‘Nocebo effect’ may explain many cases of statin intolerance: SAMSON

 So now your doctor has clinical proof that YOU are to blame for those side effects. Hope that makes you feel better.

‘Nocebo effect’ may explain many cases of statin intolerance: SAMSON

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Patients who developed symptoms within 2 weeks of statin initiation reported similar side effects while on placebo, suggesting a large proportion of burden owed to the nocebo effect, according to findings from the SAMSON trial.

According to research presented at the virtual American Heart Association Scientific Sessions, when this nocebo effect was revealed to these patients, who had initially discontinued statin therapy due to adverse effects, half were open to resuming treatment.

“We frequently see patients who have stopped taking statins due to the side effects. Yet, studies actually show that more than half of patients abandoned statins completely within 2 years of starting them; and yet, in placebo-controlled trials, no more people stopped statins than stopped placebos,” James P. Howard, PhD, Wellcome Trust PhD Fellow and cardiology registrar at Imperial College London, said during his presentation. “So, we designed a study to solve this contradiction because a patient who is suffering side effects from statin tablets gains no help from the experience of thousands of other people in placebo-controlled trials because their key question is, ‘Why is this happening to me?’”

The study was simultaneously published in The New England Journal of Medicine.

For this double-blind, three-group, n-of-1 trial, investigators enrolled 60 patients (mean age, 66 years; 58% men; 90% white) who had previously discontinued statins due to side effects that occurred within 2 weeks of therapy initiation of treatment to determine whether symptoms attributed to discontinuation were caused by a statin or placebo.

Participants were given four bottles of atorvastatin 20 mg, four bottles of a placebo and four empty bottles, with each bottle taken for a 1-month period according to a random sequence.

Via smartphone app, participants reported daily symptom scores, which ranged from 0, or no symptoms, to 100, the worst imaginable symptoms.

“If the side effects were caused by the statin molecules, the placebo months would have been down at the level of the empty months. But if the side effects were caused by the nocebo effect, then the placebo would be just as bad as the statin,” Howard said during the presentation. “We also wanted to see if taking part in SAMSON could directly help our patients. So, we asked each of them 6 months after they finished this trial if they had been able to go back onto clinical status, which they had previously believed they needed to abandon for good.”

Symptom severity

Overall, the mean reported symptom severity scores were:

• 8 for no treatment (95% CI, 4.7-11.3);
• 15.4 for placebo (95% CI, 12.1-18.7); and
• 16.3 for statin therapy (95% CI, 13-19.6).

Investigators found that difference in symptom severity reported for placebo compared with statin therapy was not clinically significant (P < .388); however, side effect severity was significant for both stain and placebo compared with no treatment (P for both < .001).

According to the results, the calculated nocebo ratio was 0.9.

“What does SAMSON tell us? SAMSON leaves no doubt that patients rarely do get side effects from statin tablets, [but] 90% of this burden is elicited by placebo tablets too,” Howard said during the presentation. “Therefore, the most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking tablets and not the statin contained within.”

Understanding nocebo and resuming therapy

In addition, 6 months after the conclusion of the trial, half of all participants resumed statin therapy.

“Regarding what SAMSON will change; first, patients need to be taken seriously when they report side effects,” Howard said. “Second, because this n-of-1 design has built-in no-tablet periods, participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect, and this led to half of them happily restarting statins. Finally, we hope that this novel study will be able to help our patients and other researchers answer questions about medications in their own fields. We believe that SAMSON could be a truly seminal trial design.”

Discussant Francine K. Welty, MD, PhD, associate professor of medicine at Harvard Medical School and cardiologist at Beth Israel Deaconess Medical Center, said during the press conference: “The most important implication is those with symptoms within 2 weeks of starting the statins should be reassured that about half will be able to successfully restart. In practice, many patients do develop symptoms later than 2 weeks, so these findings cannot be generalized to them. For example, in the SEARCH trial, 85% to 90% develop their myalgias after the first month of treatment.

“There was also no wash-out period between each 1-month treatment arm,” Welty said. “If subjects developed symptoms during atorvastatin and then went to placebo, there is possibility that there was carryover of symptoms into the placebo arm.”

Reference:

• Wood FA, et al. N Engl J Med. 2020;doi:10.1056/NEJMc2031173.